Ectodermal dysplasias (ED) are a group of more than 150 clinically distinct disorders, of which the underlying genes have been positively identified in only two. Many of these syndromes are rare, and can manifest with variable combinations and severity of defects in the development of the four major epidermal appendages: sweat glands, hair, teeth and nails. The conditions have been shown to be attributable to autosomal dominant, autosomal recessive and X-linked dominant and recessive genes. The classical X-linked anhydrotic ectodermal dysplasia (EDA) was linked to Xq12-q13.1, and mutations were identified in a novel transmembrane protein of unknown function, called EDA. More recently, mutations in the plakophilin I gene were found to result in a form of ectodermal dysplasia with skin fragility. In addition to these forms, four other phenotypes have been linked to different chromosomal loci, though no underlying genes or mutations have yet been identified. These include 1) Clouston syndrome in the pericentric region of chromosome 13; 2) EEC (ectrodactyly, ectodermal dysplasia) syndrome to chromosome 7q11.2-21.3; 3) Split hand/split foot malformation to chromosome 7q21.2-q21.3; and most recently 4) (autosomal dominant hypohidrotic ectodermal dysplasia) to chromosome 2q11-q13. We have had an interest in isolated disorders of the hair and teeth, and in this Pilot and Feasibility study, we propose linkage studies and gene discovery in three families with ectodermal dysplasias, with the goal of understanding additional pathways of gene expression in the development of ectodermal structures.